[HTML][HTML] Signaling pathways in insulin action: molecular targets of insulin resistance

JE Pessin, AR Saltiel - The Journal of clinical investigation, 2000 - Am Soc Clin Investig
JE Pessin, AR Saltiel
The Journal of clinical investigation, 2000Am Soc Clin Investig
Several mechanisms could account for the greater than expected degree of insulin
resistance in these individuals. First, because the insulin receptor precursor can form
hybrids, the mutant receptor might function in a dominant-interfering manner, inhibiting the
function of the normal allele. However, an interesting alternative model has emerged from
the study of Insr knockout mice. The developmental characteristics of homozygous insulin
receptor null mice are different from those of the compound receptor mutations in humans …
Several mechanisms could account for the greater than expected degree of insulin resistance in these individuals. First, because the insulin receptor precursor can form hybrids, the mutant receptor might function in a dominant-interfering manner, inhibiting the function of the normal allele. However, an interesting alternative model has emerged from the study of Insr knockout mice. The developmental characteristics of homozygous insulin receptor null mice are different from those of the compound receptor mutations in humans, and these mice die shortly after birth owing to extreme insulin resistance (4, 5). Heterozygous mice, carrying only one disrupted Insr allele are phenotypically normal, with no apparent defects in insulin signaling. Similarly, heterozygous knockout mice lacking a single allele of the gene for the insulin receptor substrate protein IRS1 lack any significant phenotype, whereas homozygous disruption of the IRS1 gene results in a mild form of insulin resistance (6, 7). IRS1–/–mice do not become diabetic, presumably owing to pancreatic β− cell compensation. Nevertheless, mice that are doubly heterozygous for these null alleles (Insr–/+ IRS1–/+) develop both insulin resistance and diabetes (8), indicating that development of diabetes can be a polygenic, multihit process. At least in mice, then, mild defects in several genes can generate insulin resistance and diabetes. Although defects in the INSR gene are too rare in the general population to account for garden-variety insulin resistance, the possibility remains that a reduction in insulin receptor levels, which by itself has no effect, can interact with other downstream alterations to generate insulin resistance. In either case, these data strongly argue for a postinsulin receptor defect (s) as a primary site leading to peripheral insulin resistance.
In addition to tyrosine autophosphorylation, the insulin receptor is also subjected to β-subunit serine/threonine phosphorylation. Data from some experimental models suggest that this modification allows receptor function to be attenuated. Thus, in vitro studies show that the tyrosine kinase activity of the insulin receptor decreases as a consequence of serine/threonine phosphorylation. The chronic elevation in insulin levels that occurs as a result of insulin resistance might stimulate the relevant serine kinases, perhaps through the IGF-1 receptor, which can also be stimulated by high concentrations of insulin Such an interaction could provide a mechanism for a vicious cycle of insulin-induced insulin resistance. Similarly, counter-regulatory hormones and cytokines can activate serine kinases, particularly protein kinase C (PKC), which has been implicated in the development of peripheral insulin resistance. Several PKC isoforms are chronically activated in human and rodent models of insulin resistance (9–11). These kinases can catalyze the serine or threonine phosphorylation of the insulin receptor or its substrates. Pharmacologic inhibition of PKC activity or reduction in PKC expression enhances insulin sensitivity and insulin receptor tyrosine kinase activity (12).
The Journal of Clinical Investigation